Dana Mathews

β-Amyloid burden in healthy aging Regional distribution and cognitive consequences

Objective: Several lines of evidence suggest that pathologic changes underlying Alzheimer disease (AD) begin years prior to the clinical expression of the disease, underscoring the need for studies of cognitively healthy adults to capture these early changes. The overall goal of the current study was to map the cortical distribution of &bgr;-amyloid (A&bgr;) in a healthy adult lifespan sample (aged 30–89), and to assess the relationship between elevated amyloid and cognitive performance across multiple domains. Methods: A total of 137 well-screened and cognitively normal adults underwent A&bgr; PET imaging with radiotracer 18F-florbetapir. A&bgr; load was estimated from 8 cortical regions. Participants were genotyped for APOE and tested for processing speed, working memory, fluid reasoning, episodic memory, and verbal ability. Results: A&bgr; deposition is distributed differentially across the cortex and progresses at varying rates with age across cortical brain regions. A subset of cognitively normal adults aged 60 and over show markedly elevated deposition, and also had a higher rate of APOE ε4 (38%) than nonelevated adults (19%). A&bgr; burden was linked to poorer cognitive performance on measures of processing speed, working memory, and reasoning. Conclusions: Even in a highly selected lifespan sample of adults, A&bgr; deposition is apparent in some adults and is influenced by APOE status. Greater amyloid burden was related to deleterious effects on cognition, suggesting that subtle cognitive changes accrue as amyloid progresses. GLOSSARY: A&bgr;: &bgr;-amyloid AD: Alzheimer disease DLBS: Dallas Lifespan Brain Study DLPFC: dorsolateral prefrontal cortex ETS: Educational Testing Service FWHM: full width at half maximum GLM: general linear model MCI: mild cognitive impairment OFC: orbital-frontal cortex ROI: region of interest SUVR: standardized uptake value ratio WAIS: Wechsler Adult Intelligence Scale

Activation of the insular cortex during dynamic exercise in humans

1 The insular cortex has been implicated as a region of cortical cardiovascular control, yet its role during exercise remains undefined. The purpose of the present investigation was to determine whether the insular cortex was activated during volitional dynamic exercise and to evaluate further its role as a site for regulation of autonomic activity. 2 Eight subjects were studied during voluntary active cycling and passively induced cycling. Additionally, four of the subjects underwent passive movement combined with electrical stimulation of the legs. 3 Increases in regional cerebral blood flow (rCBF) distribution were determined for each individual using single‐photon emission‐computed tomography (SPECT) co‐registered with magnetic resonance (MR) images to define exact anatomical sites of cerebral activation during each condition. 4 The rCBF significantly increased in the left insula during active, but not passive cycling. There were no significant changes in rCBF for the right insula. Also, the magnitude of rCBF increase for leg primary motor areas was significantly greater for both active cycling and passive cycling combined with electrical stimulation compared with passive cycling alone. 5 These findings provide the first evidence of insular activation during dynamic exercise in humans, suggesting that the left insular cortex may serve as a site for cortical regulation of cardiac autonomic (parasympathetic) activity. Additionally, findings during passive cycling with electrical stimulation support the role of leg muscle afferent input towards the full activation of leg motor areas.

Metabolism of [U-13 C]glucose in human brain tumors in vivo.

Glioblastomas and brain metastases demonstrate avid uptake of 2‐[18F]fluoro‐2‐deoxyglucose by positron emission tomography and display perturbations of intracellular metabolite pools by 1H MRS. These observations suggest that metabolic reprogramming contributes to brain tumor growth in vivo. The Warburg effect, excess metabolism of glucose to lactate in the presence of oxygen, is a hallmark of cancer cells in culture. 2‐[18F]Fluoro‐2‐deoxyglucose‐positive tumors are assumed to metabolize glucose in a similar manner, with high rates of lactate formation relative to mitochondrial glucose oxidation, but few studies have specifically examined the metabolic fates of glucose in vivo. In particular, the capacity of human brain cancers to oxidize glucose in the tricarboxylic acid cycle is unknown. Here, we studied the metabolism of human brain tumors in situ. [U‐13 C]Glucose (uniformly labeled glucose, i.e. d‐glucose labeled with 13 C in all six carbons) was infused during surgical resection, and tumor samples were subsequently subjected to 13C NMR spectroscopy. The analysis of tumor metabolites revealed lactate production, as expected. We also determined that pyruvate dehydrogenase, turnover of the tricarboxylic acid cycle, anaplerosis and de novo glutamine and glycine synthesis contributed significantly to the ultimate disposition of glucose carbon. Surprisingly, less than 50% of the acetyl‐coenzyme A pool was derived from blood‐borne glucose, suggesting that additional substrates contribute to tumor bioenergetics. This study illustrates a convenient approach that capitalizes on the high information content of 13C NMR spectroscopy and enables the analysis of intermediary metabolism in diverse cancers growing in their native microenvironment. Copyright

Sentinel lymph node biopsy, an alternative to elective axillary dissection for breast cancer

BACKGROUND Axillary metastases remain an important prognostic indicator in breast cancer. Axillary lymphadenectomy (ALND) carries significant morbidity and is unnecessary in most patients with early breast cancer; thus, sentinel lymph node (SLN) biopsy has been advocated for axillary staging. We studied the SLN identification rate and its accuracy in predicting axillary metastases. METHODS One hundred nineteen women with breast carcinoma underwent SLN and ALND. Lymphoscintigraphy was performed using Technetium99 sulfur colloid supplemented by Isosulfan blue dye. Hematoxylin/eosin-stained lymph node sections were examined by light microscopy. RESULTS The SLN identification rate was 81%. One SLN was negative (1%) in a patient with axillary disease. SLN histology correctly predicted the absence of axillary disease in 98.6%. Sensitivity, specificity, and positive and negative predictive values were 96%, 100%, 100%, and 99%, respectively. CONCLUSIONS Sentinel lymph node biopsy accurately predicts total axillary status and is valuable in the surgical staging of breast cancer.

Interdisciplinary evaluation of cerebral hemodynamics in the treatment of arteriovenous fistulae associated with giant varices

The techniques for the treatment of intracranial arteriovenous fistulae include angiographic balloon occlusion of the fistula as well as direct surgical attack. Regardless of the method, the occurrence of severe hyperemia caused by a lack of autoregulation after obliteration of the fistula remains a significant concern. We report the use of single photon emission computed tomography and transcranial Doppler studies to assess the occurrence of hyperemia during trial balloon occlusion of such fistulae in two patients. Single photon emission computed tomography and transcranial Doppler studies confirmed the lack of hyperemia during the test occlusion, allowing consideration of treatment plans involving acute fistula occlusion without the difficulty imposed by gradual occlusion and permitting a more accurate evaluation of risk. The purpose of this report is to illustrate how clinical evaluation of intracranial hemodynamics can contribute significantly to treatment decisions.

Positron emission tomography in prostate and renal cell carcinoma.

Purpose of review The present review addresses technical improvements in [18F]deoxyglucose positron emission tomography (PET) and new tracer developments that may increase detection in prostate cancer and renal cell carcinoma. In addition, we discuss the future of molecular imaging in prostate cancer. Recent findings PET has proven useful in imaging primary and metastatic cancer in a variety of tumor types. Previous work suggested that the most common radiopharmaceutical used in PET imaging - [18F]deoxyglucose - has a limited role in diagnosing primary prostate cancer and renal cell carcinoma. Technical improvements in scanning techniques and in PET scanners have increased detection of primary and metastatic lesions in both tumor types with [18F]deoxyglucose PET, as compared with previous studies. These improvements include increased scanner resolution and improved processing algorithms. In both prostate and renal cell carcinoma, however, better detection may result from the development of new tracers, particularly those that are not excreted into renal collecting systems. Labeled choline shows promise, as does [11C]acetate. New tracers for prostate cancer could be developed to detect changes that signal malignant transformation, as well as tracers that could show expression of genes administered for therapy. Summary Technical improvements and the development of new tracers will probably make PET imaging a viable diagnostic tool in prostate cancer and renal cell carcinoma.

A solitary hyperfunctioning thyroid nodule harboring thyroid carcinoma: review of the literature

Hyperfunctioning nodules of the thyroid are thought to only rarely harbor thyroid cancer, and thus are infrequently biopsied. Here, we present the case of a patient with a hyperfunctioning thyroid nodule harboring thyroid carcinoma and, using MEDLINE literature searches, set out to determine the prevalence of and characteristics of malignant “hot” nodules as a group. Historical, biochemical and radiologic characteristics of the case subjects and their nodules were compared to those in cases of benign hyperfunctioning nodules. A literature review of surgical patients with solitary hyperfunctioning thyroid nodules managed by thyroid resection revealed an estimated 3.1% prevalence of malignancy. A separate literature search uncovered 76 cases of reported malignant hot thyroid nodules, besides the present case. Of these, 78% were female and mean age at time of diagnosis was 47 years. Mean nodule size was 4.13 ± 1.68 cm. Laboratory assessment revealed T3 elevation in 76.5%, T4 elevation in 51.9%, and subclinical hyperthyroidism in 13% of patients. Histological diagnosis was papillary thyroid carcinoma (PTC) in 57.1%, follicular thyroid carcinoma (FTC) in 36.4%, and Hurthle cell carcinoma in 7.8% of patients. Thus, hot thyroid nodules harbor a low but non-trivial rate of malignancy. Compared to individuals with benign hyperfunctioning thyroid nodules, those with malignant hyperfunctioning nodules are younger and more predominantly female. Also, FTC and Hurthle cell carcinoma are found more frequently in hot nodules than in general. We were unable to find any specific characteristics that could be used to distinguish between malignant and benign hot nodules.

Quantitative cerebral blood flow imaging in a patient with the Heidenhain variant of Creutzfeldt-Jakob disease.

Purpose This report describes quantitative SPECT cerebral blood flow (CBF) changes in a patient with the confirmed Heidenhain variant of Creutzfeldt-Jakob disease. Materials and Methods A 60-year-old man reported visual disturbances, including left hemianopsia. An electroencephalogram, magnetic resonance imaging, cerebral arteriogram, and quantitative SPECT CBF imaging with Xe-133, with and without acetazolamide, were performed. After the patient’s death, an autopsy was performed. Results The electroencephalographic findings were nonspecific, those of magnetic resonance imaging were normal, and the cerebral arteriogram showed minimal atherosclerosis. However, the SPECT scan revealed marked depression of perfusion in the parietal and occipital cortices that did not change with the administration of acetazolamide. Autopsy results were consistent with CJD. Conclusions Although there is no consistent pattern of CBF changes that is characteristic of Creutzfeldt-Jakob disease, the Heidenhain variant of that disease may be an exception. Clinical symptoms include profound changes in vision, and the pattern of CBF changes in the patient described here included depression of perfusion in areas of primary and associated visual cortex. Also of interest is the finding that although other imaging did not reveal an abnormality, the CBF changes were marked. In addition, vasoreactivity is poor in response to acetazolamide, a finding that occurs only late in other neuronal degenerative conditions such as Alzheimer’s disease.

Behavioral effects of pergolide mesylate on food intake and body weight

In a crossover design experiment, pergolide mesylate significantly suppressed food intake and body weight in spayed female rats. Inhibition of food intake by a constant dose of pergolide progressively diminished with repeated administrations. Pergolide continued to suppress body weight with no indications of tolerance. When pergolide was discontinued, body weight increased sufficiently to compensate for the loss and failure to gain during drug treatment. A second experiment investigated the observation that animals injected first with vehicle showed greater anorexia when subsequently injected with pergolide than did animals injected first with pergolide. In addition, tolerance was further assessed by administering on two occasions a higher dose of pergolide. Following chronic pergolide treatment, this dose was insufficient to reinstate anorexia; however, after a period of abstinence, this dose produced anorexia comparable to that observed at the beginning of pergolide treatment. Due to pergolide mesylates action as a postsynaptic dopamine agonist, a dopaminergic neural system is implicated in pergolide induced anorexia.

Inframanubrial Parathyroid Glands in Patients with Primary Hyperparathyroidism: Alternatives to Sternotomy

Deep inframanubrial parathyroid tumors have traditionally been excised through a median sternotomy. With the advent of minimally invasive surgical access, we chose to examine the treatment options and outcomes of patients with inframanubrial mediastinal parathyroid tumors. Patients with primary hyperparathyroidism seen at a university medical center over a 12-year period were retrospectively reviewed. The utility of localization studies, methods of treatment, complications, and outcomes were examined in patients with a parathyroid tumor located in the mediastinum inferior to the manubrium. Patients with parathyroid adenomas located at the thoracic inlet were excluded. Sixteen patients with inframanubrial mediastinal tumors were treated during the study period. Altogether, 81% of the patients had undergone at least one prior neck exploration for primary hyperparathyroidism. Preoperative calcium and parathyroid hormone levels were 12.4 ± 0.36 mg/dl and 273 ± 70 pg/ml, respectively. Localization studies identified mediastinal parathyroid adenomas in the following locations: anterior mediastinum (n = 8), middle mediastinum (n = 7), posterior mediastinum (n = 1). Mediastinal computed tomography and technetium-sestamibi scans demonstrated the best sensitivity, 92% and 85%, respectively. Seven patients underwent successful excision of the mediastinal adenoma by transcervical mediastinal exploration with the Cooper retractor. The other patients underwent angiographic ablation (n = 4), anterior mediastinotomy (n = 3), video-assisted thoracoscopy (VATS) (n = 1), and VATS plus thoracotomy (n = 1). The mean hospital stay for the study group was 2.9 ± 0.7 days. The complication rate was 25%. All patients were normocalcemic after a mean follow-up of 15 ± 7 months. Most inframanubrial mediastinal parathyroid tumors can be successfully managed without median sternotomy.